Summary of work: Beta-amyloid peptide, a product of metabolism of amyloid precursor protein (APP), has been implicated in neurodegeneration in Alzheimer's disease. Exposure of pheochromocytoma 12 (PC12) cells in tissue culture to beta-amyloid peptide (1-40) increases membrane choline and calcium permeability, measured by patch clamping and radiofluxes. The choline effect is ascribed to formation of de-novo carriers for choline or to disruption of endogenous choline transporter in the cell membrane. A comparable effect in Alzheimer's disease could interfere with production and release of the neurotransmitter acetylcholine, deplete energy stores of cholinergic neurons and account for the observed loss of cholinergic neurons. Exposing cells to fluorescent labeled beta-amyloid peptide (1-40) and (1-42) showed peptide uptake in the cell membrane. Beta-amyloid peptide(1-40) synthesized from D amino-acid stereo-isomers showed comparable uptake to L amino acid beta amyloid peptide into the cell membrane. Under the electron microscope, cells treated with beta-amyloid showed time-dependent and concentration dependent ultrastructural cup-like double membrane invaginations in the membrane, and an increased number and size of lysosomes within the cytoplasm. Freeze-fracture studies showed that the distribution of density of the intramembranous particles (IMP) of diameter >9 nm was shifted towards the larger sizes in the beta-amyloid treated cells compared with control cells. Increased numbers of large diameter IMPs in PC12 cells could represent modifications to existing transmembrane receptors or channels.